Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The centrosome is important for microtubule organization and cell cycle progression in animal cells. Recently, mutations in the centrosomal protein, pericentrin, have been linked to human microcephalic osteodysplastic primordial dwarfism (MOPD II), a rare genetic disease characterized by severe growth retardation and early onset of type 2 diabetes among other clinical manifestations. While the link between centrosomal and cell cycle defects may account for growth deficiencies, the mechanism linking pericentrin mutations with dysregulated glucose homeostasis and pre-pubertal onset of diabetes is unknown. In this report we observed abundant expression of pericentrin in quiescent pancreatic beta-cells of normal animals which led us to hypothesize that pericentrin may have a critical function in beta-cells distinct from its known role in regulating cell cycle progression. In addition to the typical centrosome localization, pericentrin was also enriched with secretory vesicles in the cytoplasm. Pericentrin overexpression in beta-cells resulted in aggregation of insulin-containing secretory vesicles with cytoplasmic, but not centrosomal, pericentriolar material and an increase in total levels of intracellular insulin. RNAi- mediated silencing of pericentrin in secretory beta-cells caused dysregulated secretory vesicle hypersecretion of insulin into the media. Together, these data suggest that pericentrin may regulate the intracellular distribution and secretion of insulin. Mice transplanted with pericentrin-depleted islets exhibited abnormal fasting hypoglycemia and inability to regulate blood glucose normally during a glucose challenge, which is consistent with our in vitro data. This previously unrecognized function for a centrosomal protein to mediate vesicle docking in secretory endocrine cells emphasizes the adaptability of these scaffolding proteins to regulate diverse cellular processes and identifies a novel target for modulating regulated protein secretion in disorders such as diabetes.
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PMID:A novel role for the centrosomal protein, pericentrin, in regulation of insulin secretory vesicle docking in mouse pancreatic beta-cells. 2067 97

Microcephalic or Majewski's osteodysplastic primordial dwarfism type II (MOPD II) represents the most common type of primordial dwarfism. Adult height is typically about one meter and short stature is becoming mildly disproportionate over time with mild skeletal anomalies. Mental development is usually borderline or within the low normal range but cerebrovascular events that are common in childhood can result in significant cognitive impairment and cerebral palsy. Despite cerebrovascular insults, cardiomyopathy and early onset type 2 diabetes contribute to early mortality and morbidity. Common minor clinical features are truncal obesity, high pitched voice, microdontia and pigmentary changes. MOPD II is caused by autosomal recessive loss of function mutations in the PCNT gene encoding for a key centrosomal protein. There is clinical overlap with the so called Seckel syndrome, a heterogeneous group of entities with at least four different gene loci known to date.
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PMID:The shortest of the short: pericentrin mutations and beyond. 2139 79